Master Regulators of Muscle Atrophy: Role of Costamere Components

Abstract

The loss of muscle mass and force characterizes muscle atrophy in several different conditions, which share the expression of atrogenes and the activation of their transcriptional regulators. However, attempts to antagonize muscle atrophy development in different experimental contexts by targeting contributors to the atrogene pathway showed partial effects in most cases. Other master regulators might independently contribute to muscle atrophy, as suggested by our recent evidence about the co-requirement of the muscle-specific chaperone protein melusin to inhibit unloading muscle atrophy development. Furthermore, melusin and other muscle mass regulators, such as nNOS, belong to costameres, the macromolecular complexes that connect sarcolemma to myofibrils and to the extracellular matrix, in correspondence with specific sarcomeric sites. Costameres sense a mechanical load and transduce it both as lateral force and biochemical signals. Recent evidence further broadens this classic view, by revealing the crucial participation of costameres in a sarcolemmal “signaling hub” integrating mechanical and humoral stimuli, where mechanical signals are coupled with insulin and/or insulin-like growth factor stimulation to regulate muscle mass. Therefore, this review aims to enucleate available evidence concerning the early involvement of costamere components and additional putative master regulators in the development of major types of muscle atrophy.

The Dystrophin Node as Integrator of Cytoskeletal Organization, Lateral Force Transmission, Fiber Stability and Cellular Signaling in Skeletal Muscle

“…Both proposed protein interactions provide key hubs for cellular signaling mechanisms within contractile fibers, such as organization of caveolae and the regulation of skeletal muscle size. Dystrophin-associated nitric oxide synthase, the enzyme responsible for the production of the key signaling molecule nitric oxide, was shown to play a regulatory role in costameres [132] and is involved in muscle fatigue, muscular atrophy and certain forms of muscular dystrophy [36,133,134]. In skeletal muscle tissues, nitric oxide levels are low under resting conditions and the production rate of this signaling molecule is greatly enhanced during repetitive muscle contractions.…”

The Critical Role of Oxidative Stress in Sarcopenic Obesity

“…Another redox-sensitive transcription factor is nuclear factor kappa B (NF-κB), which dramatically increases muscle activity in sarcopenia, metabolic syndrome, and obesity [83,113]. NF-κB regulates the expression of myokines such as TNF-α and IL-6, inducing chronic low-grade inflammation and apoptosis.…”

Chronic Ouabain Prevents Na,K-ATPase Dysfunction and Targets AMPK and IL-6 in Disused Rat Soleus Muscle

“…The signaling mechanism involved by the skeletal muscle motor dysfunction is rather complex and remains to be elucidated in details [45,[49][50][51]. We found here two-fold increase in the relative phosphorylation level of AMPK in skeletal muscle from rats after chronic pre-treated with ouabain followed by the HS.…”